Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• the group of inventions relates to medicine, namely to pharmaceutics and the development of compositions of pharmaceutical preparations, containing antibiotics and prebiotics, for correcting the composition of the intestinal microflora during antibiotic therapy.
• antibiotics The therapeutic action of broad-spectrum antibiotics is as a rule accompanied by disturbances involving the gastrointestinal tract, connected with negative action of the antibiotic on the microflora of the large intestine.
• Antibiotics have a strong negative influence on the permeability of biological membranes to ammonium ions in the large intestine.
• antibiotics suppress not only pathogenic, but also useful microflora of the digestive tract, lead to disturbance of homeostasis and promote the development of dysbiosis and allergies. Disturbed equilibrium in the microbiocenosis of the intestine leads in many cases to disturbances of the immune system and active multiplication of unicellular fungi, which actively colonize the intestine.
• the normal intestinal microflora is a necessary condition for digestion of food and assimilation of nutrients, as well as it serves as a barrier to exogenous infection; it participates in detoxication of toxic metabolites, restriction of the multiplication of pathogenic and opportunistic microorganisms that have got into the intestine.
• microflora in the gastrointestinal-tract arise starting from the distal part of the small intestine, where the secretions of the stomach and pancreas do not reach, as well as the components of the bile, the bacteriostatic and bactericidal effects of which become weaker as the large intestine is approached.
• pathogenic agents of intestinal infections or opportunistic microorganisms that enter the body can quickly colonize the mucosa of the small and large intestine, destroying epithelial cells and displaying pronounced antagonism with respect to the indigenous microflora.
• Inflammation develops, leading to reduced production of short-chain fatty acids, which inhibit the growth of pathogenic microorganisms. This occurs during antibiotic therapy with broad-spectrum preparations. Even partial loss of the intrinsic intestinal microflora leads to serious consequences for the organism and requires specific treatment.
• Such treatment can be carried out, in particular, by prescribing various probiotics, which are not always compatible with the normal microflora and over a period of several days they may be eliminated from the intestine.
• probiotics include at first and foremost the ability of probiotics to modulate immune inflammation. For example, it is known that about 10% of workers of factories producing bacterial and immunobiological preparations (probiotics), after several years of the work get allergic diseases.
• Prebiotics are indigestible components of food, which promote improvement of health by selective stimulation of the growth and/or metabolic activity of one or more groups of bacteria living in the large intestine.
• Carbohydrate prebiotics in contrast to probiotics, are not digested in the stomach and are not absorbed, but reach the large intestine unchanged, because their structure has unusual beta-glycosidic bonds, which are not hydrolyzed by the human organism owing to the absence of specific beta-glycosidases.
• prebiotics can selectively stimulate the growth and multiplication of lactobacilli and bifidobacteria, i.e.
• Prescribing combination therapy including prebiotics mean to eliminate atrophic processes in the mucosa of the large intestine and dystrophic changes of the epithelium with restoration of its functionality.
• prebiotics are prescribed when the symptoms of dysbiosis have already appeared, particularly in the form of diarrhea and flatulence.
• prebiotics begin to be taken after antibiotic therapy has been carried out, the useful microflora has been strongly disrupted or is practically unviable.
• a drawback of this composition is that the commonly used lactulose preparations contain a considerable amount of admixtures (lactose, galactose, fructose), which can stimulate the growth of pathogenic and opportunistic species of microorganisms living parasitically in the intestine.
• Drawbacks of this composition are a narrow range of application, low specificity of stimulant action on the main species of the indigenous microflora, nonoptimal weight ratio (lack of balance) of antibiotic and fructan, nonoptimal degree of dispersion (particle size), nonoptimal degree of polymerization of the prebiotic, at which the level of fermentation of carbohydrates and the antibacterial action of the product are reduced. There is reduced therapeutic-prophylactic effect from using the composition, as well as reduced calcium absorption and bone mineralization. Moreover, said composition is characterized by complexity of the production process and insufficient efficacy in application.
• the technical object of the group of inventions is the creation of an effective pharmaceutical composition and a method of preventing dysbiosis, while extending the arsenal of pharmaceutical compositions and methods of preventing dysbiosis.
• the technical result that enables this object to be achieved comprises expanding the range of application of a composition of prebiotics and antibiotics, by the inclusion of more effective antibacterial preparations for oral administration (fluoroquinolones, ansamycins etc.) in the composition and the elimination of side-effects.
• Effective utilization of the prebiotic component of the composition in the intestine is provided by administering oligosaccharides with an optimal degree of polymerization and optimal proportions of the components with the necessary degree of dispersion (particle size).
• the essence of the invention with respect to a pharmaceutical composition for preventing intestinal dysbiosis during antibiotic therapy, destined for oral use, contains an antibiotic and a prebiotic, moreover the antibiotic and the prebiotic are incorporated in the form of powder, and the prebiotic comprises an oligosaccharide selected from the group comprising fructooligosaccharides, galactooligosaccharides, xylooligosaccharides, maltooligosaccharides and isomaltooligosaccharides with degree of polymerization from 2 to 10, particle size up to 0.3 mm and purity of at least 95%, and antibiotic with particle size from 20 to 200 ⁇ m, moreover the antibiotic and the oligosaccharide are incorporated in a fixed composition at a weight ratio from 1:1 to 1:100, respectively.
• composition for improving the organoleptic and consumer properties, selected from the groups: fillers, taste correctants, flavorings, and odoriferous substances.
• excipients for improving the organoleptic and consumer properties, selected from the groups: fillers, taste correctants, flavorings, and odoriferous substances.
• the composition is produced in a pharmaceutical form suitable for oral use, selected from the group comprising capsules, tablets, powders, pills, sugar-coated pills, granules, sachets, gels, pastes, syrups, emulsions, suspensions, solutions.
• the essence of the invention with respect to a pharmaceutical composition for preventing intestinal dysbiosis during antibiotic therapy, destined for oral use, according to a second embodiment contains an antibiotic and a prebiotic, said antibiotic and said prebiotic being included in the form of powder, moreover the antibiotic, selected from the group comprising beta-lactams, including combinations of beta-lactams with inhibitors of bacterial beta-lactamases, azalides, fluoroquinolones, amphenicols, glycopeptides, ansamycins, nitrofurans, derivatives of phosphonic acid, cycloserine, trimetoprim, is included with particle size from 20 to 200 ⁇ m, and oligosaccharide with degree of polymerization from 2 to 10 is included as prebiotic, moreover the antibiotic and the oligosaccharide are included in the composition at a weight ratio from 1:1 to 1:100.
• the antibiotic selected from the group comprising beta-lactams, including combinations of beta-lactams with inhibitors of bacterial beta-lac
• composition for improving the organoleptic and consumer properties, selected from the group comprising fillers, taste correctants, flavorings, and odoriferous substances.
• excipients for improving the organoleptic and consumer properties, selected from the group comprising fillers, taste correctants, flavorings, and odoriferous substances.
• the composition is prepared in a pharmaceutical form suitable for oral use, selected from the group comprising capsules, tablets, powders, pills, sugar-coated pills, granules, sachets, gels, pastes, syrups, emulsions, suspensions, solutions.
• the essence of the invention with respect to the method of preventing intestinal dysbiosis during antibiotic therapy comprises administration of a fixed pharmaceutical composition containing an antibiotic and a prebiotic, said antibiotic and said prebiotic being included in the form of powder, moreover an oligosaccharide prebiotic selected from the group comprising fructooligosaccharides, galactooligosaccharides, xylooligosaccharides, maltooligosaccharides or isomaltooligosaccharides with degree of polymerization from 2 to 10, with particle size up to 0.3 mm and purity of at least 95%, and the antibiotic has a particle size from 20 to 200 ⁇ m, moreover the antibiotic and the oligosaccharide are included in a fixed composition at a weight ratio from 1:1 to 1:100, respectively, which is administered orally.
• an oligosaccharide prebiotic selected from the group comprising fructooligosaccharides, galactooligosaccharides, xylooligosaccharides, maltool
• the essence of the invention with respect to the method of preventing intestinal dysbiosis during antibiotic therapy comprises administration of a pharmaceutical composition containing an antibiotic and a prebiotic, said antibiotic and said prebiotic being included in the form of powder, the antibiotic being selected from the group comprising beta-lactams, including combinations of beta-lactams with inhibitors of bacterial beta-lactamases, azalides, fluoroquinolones, amphenicols, glycopeptides, ansamycins, nitrofurans, derivatives of phosphonic acid, cycloserine, trimetoprim and included with particle size from 20 to 200 ⁇ m, and an oligosaccharide with degree of polymerization from 2 to 10 is included as prebiotic, moreover the antibiotic and the oligosaccharide are included in the composition at a weight ratio from 1:1 to 1:100, which is taken orally.
• oligosaccharides - fructooligosugars, galactooligosugars, xylooligosugars, maltooligosugars and isomaltooligosugars not only create conditions for growth of useful bacteria, but also effectively improve the composition of the blood, and the state of the cardiovascular and immune systems.
• the human body is a multiorgan system, the cellular elements of which are specialized for performing various functions. Interaction inside the body is based on complex regulating and coordinating mechanisms involving neurohumoral and other factors. The many separate mechanisms regulating intracellular and intercellular interactions perform opposing functions, which balance one another. This leads to the establishment of a dynamic physiological balance in the body and enables the system as a whole to maintain relative dynamic equilibrium, despite changes in the surroundings and shifts arising during the activity of the organism. Disturbance of physiological balance, including that connected with disturbance of equilibrium in microbiocenosis, may be manifested as diseases of various organs.
• the proposed composition and method of use are directed to prevention or effective decrease of deviations of physiological balance, with respect to the state of the intestinal microbiocenosis under the influence of a "disturbing" factor in the form of antibiotics.
• Oligosaccharides are carbohydrates whose molecules are predominantly formed by not more than 10 monosaccharide residues. They are divided into disaccharides, trisaccharides and so on. In living organisms oligosaccharides are formed during enzymatic cleavage of polysaccharides. The microorganisms in the gut utilize oligosaccharides with the aid of their own glycosidases, and oral administration of oligosaccharides leads to increased production and intensification of the saccharolytic activity of these enzymes.
• the prebiotic - oligosaccharide in the form specified according to the present invention is used in the proposed composition simultaneously with the antibiotic and in the necessary proportions by weight, although the antibiotic suppresses pathogenic bacteria, the intrinsic microflora of the large intestine does not perish, but synchronously with the supply of oligosaccharide, hydrolyzes (ferments) the latter with formation of an effective amount of short-chain fatty acids (predominantly lactic, partially formic and acetic).
• the osmotic pressure in the large intestine increases to 6.6-8.0 atm and the pH falls below 5.0, i.e.
• Any nonliving and living matter (organism, system, organ, tissue, cell, cellular organelles and substrates etc.) has its particular spectrum of electromagnetic vibrations in a wide range from hundredths of a hertz to kilo- and mega-hertz and more complex harmonics. In normal conditions, it is accepted to call these vibrations harmonic (physiological), whereas in pathologic conditions, disharmonic (pathological) vibrations appear.
• Oligosaccharides in the form specified according to the present invention, being vegetable components, have energy components that initiate super-weak electromagnetic vibrations, which are superposed on the disharmonic vibrations introduced by the antibiotics, and at selected proportions by weight of the ingredients there is, as it were, "obliteration" of this potentially pathologic information.
• the process for preparation of the proposed composition comprises preparing specified amounts of powdered antibiotic and powdered prebiotic with a supplier-guaranteed purity of at least 95%, predrying to 2-3% moisture and mixing in the proportions specified by the present invention.
• the mixture also includes anticaking additives, flavorings, and taste correctants, and static electric charges are removed.
• packaging of the finished product is carried out, according to the dosage and the pharmaceutical form.
• compositions with the following combinations of ingredients were prepared.
• Fructooligosugars with one of the ansamycins with the oligosaccharide in the form of powder with particle size of 0.1-0.3 mm and with degree of polymerization from 4 to 10, and with the antibiotic in the form of powder with particle size of 20-140 ⁇ m, the antibiotic and the oligosaccharide being used in a weight ratio of 1:15.
• fosfomycin derivatives of phosphonic acid
• Galactooligosugars with one of the sulfanilamide preparations (Streptocid), with the oligosaccharide in the form of powder with particle size of 0.2-0.3 mm and with degree of polymerization from 2 to 6, and with the antibiotic in the form of powder with particle size of 40-150 ⁇ m, the antibiotic and the oligosaccharide being used in a weight ratio of 1:45.
• Xylooligosugars with one of the fluoroquinolones, with the oligosaccharide in the form of powder with particle size of 0.1-0.3 mm and with degree of polymerization from 2 to 8, and with the antibiotic in the form of powder with particle size of 20-120 ⁇ m, the antibiotic and the oligosaccharide being used in a weight ratio of 1:80.
• Xylooligosugars with one of the glycopeptides, with the oligosaccharide in the form of powder with particle size of 0.2-0.3 mm and with degree of polymerization from 4 to 10, and with the antibiotic in the form of powder with particle size of 160-200 ⁇ m, the antibiotic and the oligosaccharide being used in a weight ratio of 1:100.
• Xylooligosugars with one of the ansamycins with the oligosaccharide in the form of powder with particle size of 0.1-0.3 mm and with degree of polymerization from 2 to 8, and with the antibiotic in the form of powder with particle size of 20-100 ⁇ m, the antibiotic and the oligosaccharide being used in a weight ratio of 1:65.
• Xylooligosugars with one of the derivatives of phosphonic acid (fosfomycin), with the oligosaccharide in the form of powder with particle size of 0.2-0.3 mm with degree of polymerization from 4 to 10, and with the antibiotic in the form of powder with particle size of 20-100 ⁇ m, the antibiotic and the oligosaccharide being used in a weight ratio of 1:5.5.
• Xylooligosugars with one of the sulfanilamide preparations with the oligosaccharide in the form of powder with particle size of 0.1-0.3 mm and with degree of polymerization from 2 to 6, and with the antibiotic in the form of powder with particle size of 20-90 ⁇ m, the antibiotic and the oligosaccharide being used in a weight ratio of 1:2.
• composition was prepared in pharmaceutical forms suitable for oral use, in particular in the form of capsules, tablets, powders, pills, sugar-coated pills, granules, sachets, gels, pastes, syrups, emulsions, suspensions, solutions.
• the composition included pharmaceutically acceptable amounts of excipients for improving the organoleptic and consumer properties, in particular fillers, taste correctants, flavorings etc.
• test group under observation comprised 157 patients in the age range from 19 to 70 years: 75 men and 82 women.
• the diagnosis was established in outpatient conditions based on medical examination, results of laboratory and biochemical tests, ECG data, echocardiography etc.
• AST and ALT activity concentration of serum creatinine, glucose, calcium, total bilirubin, protein, serum iron, TIBC, sodium, potassium, cholesterol, uric acid, urea, albumin, activity of alkaline phosphatase and GGT, content of triglycerides, ⁇ -lipoproteins, and in addition urine analysis, microbiologic analysis of the intestinal contents and investigation of the feces were carried out.
• antibiotics with oligosaccharides according to each of these embodiments were taken by patients in test subgroups of 5-6 patients. Monitoring tests were carried out for 2 months, every 8-10 days.
• the condition of the patients in the control group had also started to improve with respect to the main disease, but 75% of patients in the first group and 50% in the second group had clear symptoms of negative effects of the antibiotics on the intestinal microbiocenoses (dysbiosis), manifested as discomfort, slight pains in the region of the large intestine, flatulence and diarrhea. In some patients the dysbiosis led to reduced appetite and sleep disturbance.
• the efficacy of the treatment was assessed before its start, during the treatment and after completion, using: biopsy of cervical mucosa, cytologic and microbiological investigation. After the first four weeks of taking the preparation, appearance of the first regions of marginal epithelization of erosions was noted, and lactobacilli and bifidobacteria appeared in the microbiocenoses of the vagina, discharges decreased considerably and painful sensations had disappeared completely.
• the data from morphological investigation after stopping intake of the preparation indicated almost complete replacement of columnar epithelium with squamous epithelium. Smears indicated a decrease in signs of inflammation.
• compositions of prebiotics and antibiotics have been expanded by including the most effective antibacterial preparations for oral administration (fluoroquinolones and ansamycins) in the composition and by eliminating side-effects.
• Effective utilization of the prebiotic component of the composition in the intestine was provided by introducing oligosaccharides with an optimal degree of polymerization and optimal proportions of the components with the necessary degree of dispersion (particle size).
• the present invention is implemented using universal equipment, which is widely used in industry.

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• 2008
  • 2008-03-18 BR BRPI0822485-4A patent/BRPI0822485A2/pt not_active Application Discontinuation
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